Interleukin-1α (IL-1α) and IL-1β are naturally occurring agonists of the type I IL-1 receptor (IL-1RI). When either of these two molecules bind to the receptor, it activates and recruits a second receptor component, the IL-1RI, accessory protein (AcP). The three-member complex (IL-1/Il-1RI/AcP) initiates a signaling cascade that includes activation and nuclear translocation of the transcription factor NF-κB. This results in the expression of many cytokines and other proteins involved in inflammation and immune responses, causing or worsening many disease processes (Barnes, Int. J. Biochem. Cell Biol. 29:867-870, 1997). Particular diseases that are believed mediated by interleukin-1 include rheumatoid arthritis (RA) and osteoarthritis (OA) (Roshak et al., Curr. Opin. Pharmacol. 2(3): 316-21, 2002).
The body has evolved at least two methods of naturally inhibiting this pathway, the type II IL-1R (Il-1RII), a so-called “decoy receptor,” and the IL-1 receptor antagonist (IL-1ra). The decoy receptor can bind both IL-1α and IL-1β but does not initiate intracellular signaling (McMahan et al., EMBO J. 10: 2821-2832, 1991). Thus, it can pull agonist out of the system and block their biologic effects. IL-1ra binds to IL-1RI with high affinity but does not activate the receptor or cause a biological response. It therefore acts a competitive antagonist to IL-1α and IL-1β (Arend, Prog. Growth Factor Res. 2(4): 193-205, 1990). Genetically engineered antagonists, such as anti-Il-1RI antibodies (Fredricks et al., Pro. Eng. Des. & Selec. 17 (1): 95-106, 2004) and IL-1ra-Fc fusion proteins (U.S. Pat. No. 6,733,753) have also been developed.
Overexpression of proinflammatory cytokines like IL-1 has been shown to play a major role in the pathogenesis of immunoinflammatory diseases such as rheumatoid arthritis (RA), a common chronic autoimmune disorder characterized by inflammation of synovial tissues, joint swelling, stiffness and pain that may progress to joint destruction (Bingham, J. Rheumatol. 29: 3-9, 2002). The clinical application of antagonizing IL-1α and IL-1β in this disease has investigated with anakinera (Kineret™), a recombinant, non-glycoslyated from of human IL-1ra. The use of this therapeutic protein has led to a reduction in frequency and severity of joint damage in RA patients (Bresnihan, Ann. Rheum. 61, ii74-ii77, 2002 and St. Clair, J. Rheumatol. 29, 22-26, 2002), however the treatment does not appear to reverse already existing damage to the cartilage or bone of the affected joints.
The fibroblast growth factor (FGF) family consists of at least twenty-three distinct members which generally act as mitogens for a broad spectrum of cell types (Ornitz and Itoh, Genom. Biol. 2(3):reviews 3005.1-3005.12, 2001). FGF18 was identified as a member of the FGF family that is most closely related to FGF8 and FGF17. Activities associated with FGF18 included stimulation of mesenchymal lineage cells, in particular cardiac myocytes, osteoblasts and chondrocytes (U.S. Pat. No. 6,352,971 and Ellsworth et al., Osteoarthritis and Cartilage, 10(4):308-320, 2002). FGF18 binds and activates FGFR4 and the “IIIc” splice variants of FGFR3 and FGFR2 (Ellsworth et al. Osteo Cartil. 10: 208-320 (2002)). It has been shown that FGFR3-IIIc and FGFR2-IIIc play a role in bone development and growth and cartilage growth (Davidson et al. J. Biol. Chem. 280:20509-20515 (2005)). Mice made homozygous null for the FGFR3 (−/−) resulted in postnatal skeletal abnormalities (Colvin et al., Nature Genet. 12:309-397, 1996 and Deng et al., Cell 84:911-921, 1996). The mutant phenotype suggests that in normal mice, FGFR-3 plays a role in regulation of chondrocyte cell division in the growth plate region of the bone (Goldfarb, Cytokine and Growth Factor Rev. 7(4):311-325, 1996). FGFR-IIIc is expressed in early mesenchymal condensates and in the developing periosteum. FGFR 2-IIIc −/− mice exhibit delayed ossification, premature loss of bone growth in the skull and long bone (Eswarakumar et al. Development 129:3783-3793 (2002)). FGF receptor mutations are also found in human chondrodysplasia and craniosynostosis syndromes (Ornitz and Marie, Genes and Dev. 16: 1446-1465, 2002).
Bone remodeling is the dynamic process by which tissue mass and skeletal architecture are maintained. The process is a balance between bone resorption and bone formation, with two cell types thought to be the major players. These cells are the osteoblast and osteoclast. Osteoblasts synthesize and deposit matrix to become new bone. The activities of osteoblasts and osteoclasts are regulated by many factors, systemic and local, including growth factors. This function provides a potential role for growth factors, such as FGF18, in disease states requiring activation of bone remodeling, such as damage to bone occurring in inflammatory diseases of the joints such as RA or osteoarthritis (OA). Other therapeutic applications for growth factors influencing bone remodeling include, for example, the treatment of injuries which require the proliferation of osteoblasts to heal, such as fractures, as well as stimulation of mesenchymal cell proliferation and the synthesis of intramembraneous bone which have been indicated as aspects of fracture repair (Joyce et al. 36th Annual Meeting, Orthopaedic Research Society, Feb. 5-8, 1990. New Orleans, La.).
Replacement of damaged articular cartilage caused either by injury or disease is a major challenge for physicians, and available treatments are considered unpredictable and effective for only a limited time. Virtually all the currently available treatments for cartilage damage focus on relief of pain, with little or no emphasis on regeneration of damaged tissues. Therefore, the majority of younger patients either do not seek treatment or are counseled to postpone treatment for long as possible. When treatment is required, the standard procedure is a total joint replacement or microfracture, a procedure that involves penetration of the subchondral bone to stimulate fibrocartilage deposition by chondrocytes. While deposition of fibrocartilage is not a functional equivalent of articular cartilage, it is at the present the best available treatment because there has been little success in replacing articular cartilage. Two approaches to stimulating deposition of articular cartilage that are being investigated are: stimulating chondrocyte activity in vivo and ex vivo expansion of chondrocytes and their progenitors for transplantation (Jackson et al., Arthroscopy: The J. of Arthroscopic and Related Surg. 12:732-738, 1996). In addition, regeneration or repair of elastic cartilage is valuable for treating injuries and defects to ear and nose. Any growth factor with specificity for chondrocytes lineage cells that stimulates those cells to grow, differentiate or induce cartilage production would be valuable for maintaining, repairing or replacing articular cartilage. FGF18 appears to promote chondrogenesis and cartilage repair in osteoarthritis in rats (Moore et al. Osteoarthritis and Cartilage, 13:623-631 (2005)) and thus, may be useful for repairing damaged cartilage.
Thus, there exists a need in the art for a method of treating a disease, such as immunoinflammatory diseases mediated by interleukin-1, that involves both blocking the inflammatory action of IL-1 and the repair of cartilage and bone through stimulation of mesenchmally-derived cells such as chondrocytes, osteocytes, and nervous tissue and their progenitors.